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Efficacy of Initial Antiretroviral Therapy for HIV-1 Infection in Adults: A Systematic Review and Meta-Analysis of 114 Studies with up to 144 Weeks' Follow-Up
Frederick J. Lee, Janaki Amin, Andrew Carr
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0097482
Abstract: Background A comprehensive assessment of initial HIV-1 treatment success may inform study design and treatment guidelines. Methods Group-based, systematic review and meta-analysis of initial antiretroviral therapy studies, in adults, of ≥48 weeks duration, reported through December 31, 2012. Size-weighted, intention-to-treat efficacy was calculated. Parameters of study design/eligibility, participant and treatment characteristics were abstracted. Multivariable, random effects, linear regression models with backwards, stepwise selection were then used to identify variables associated with efficacy. Outcome Measures Antiviral efficacy (undetectable plasma viral load) and premature cessation of therapy. Results 114 studies were included (216 treatment groups; 40,124 participants; mean CD4 count 248 cells/μL [SD 81]; mean HIV-1 plasma viral load log10 4.9 [SD 0.2]). Mean efficacy across all groups was 60% (SD 16) over a mean 82 weeks' follow-up (SD 38). Efficacy declined over time: 66% (SD 16) at 48 weeks, 60% (SD 16) at 96 weeks, 52% (SD 18) at 144 weeks. The most common reason for treatment cessation was participant decision (11%, SD 6.6). Efficacy was higher with ‘Preferred’ than ‘Alternative’ regimens (as defined by 2013 United States antiretroviral guidelines): 75% vs. 65%, respectively, difference 10%; 95%CI 7.6 to 15.4; p<0.001. In 98 groups (45%) reporting efficacy stratified by pre-treatment viral load (< or ≥100,000 copies/mL), efficacy was greater for the lower stratum (70% vs. 62%, respectively, difference 8.4%; 95%CI 6.0 to 10.9; p<0.001). This difference persisted within ‘Preferred’ regimens. Greatest efficacy was associated with use of tenofovir-emtricitabine (vs. other nucleoside analogue backbones) and integrase strand transfer inhibitors (vs. other third drug classes). Conclusion Initial antiretroviral treatments for HIV-1 to date appear to have suboptimal long-term efficacy, but are more effective when commenced at plasma viral loads <100,000 copies/mL. Rising viral load should be considered an indication for starting treatment. Integrase inhibitors offer a treatment advantage (vs. other third drug classes).
Predictors of Limb Fat Gain in HIV Positive Patients Following a Change to Tenofovir-Emtricitabine or Abacavir-Lamivudine
Allison Martin, Janaki Amin, Sean Emery, David Baker, Andrew Carr, David A. Cooper, Mark Bloch
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0026885
Abstract: Background Antiretroviral treatment (cART) in HIV causes lipoatrophy. We examined predictors of anthropometric outcomes over 96 weeks in HIV-infected, lipoatrophic adults receiving stable cART randomised to tenofovir-emtricitabine (TDF-FTC) or abacavir-lamivudine (ABC-3TC) fixed dose combinations. Methodology/Principal Findings The STEAL study was a prospective trial of virologically suppressed participants randomised to either TDF-FTC (n = 178) or ABC-3TC (n = 179). Anthropometric assessment was conducted at baseline, weeks 48 and 96. The analysis population included those with baseline and week 96 data remaining on randomised therapy. Distribution of limb fat change was divided into four categories (≤0%, >0–10%, >10–20%, >20%). Baseline characteristics [demographics, medical history, metabolic and cardiovascular biomarkers] were assessed as potential predictors of change in percent subcutaneous limb fat using linear regression. 303 participants (85% of STEAL population) were included. Baseline characteristics were: mean (±SD) age 45 (±8) years; thymidine analogue nucleoside reverse transcriptase inhibitor (tNRTI) duration 4 (±3) years; limb fat 5.4 (±3.0)kg; body mass index 24.7 (±3.5) kg/m2. Mean (SD) limb fat gain to week 48 and 96 was 7.6% (±22.4) and 13.2% (±27.3), respectively, with no significant difference between groups. 51.5% of all participants had >10% gain in limb fat. Predictors of greater limb fat gain at week 96 were baseline tNRTI (10.3, p = 0.001), glucose >6 mmol/L (16.1, p = 0.04), higher interleukin 6 (IL-6) (2.8, p = 0.004) and lower baseline limb fat (3.8–6.4 kg – 11.2; >6.4 kg – 15.7, p trend<0.001). Conclusions/Significance Modest peripheral fat gain occurred with both TDF-FTC and ABC-3TC. Baseline factors associated with more severe lipodystrophy (lipoatrophy, baseline tNRTI, raised IL6, and glucose) predicted greater limb fat recovery at 96 weeks.
Trends in all cause and viral liver disease-related hospitalizations in people with hepatitis B or C: a population-based linkage study
Heather F Gidding, Gregory J Dore, Janaki Amin, Matthew G Law
BMC Public Health , 2011, DOI: 10.1186/1471-2458-11-52
Abstract: HBV and HCV notifications were linked to their hospital (July 2000-June 2006), HIV and death records. Standardized hospitalization ratios (SHRs) were calculated using rates for the NSW population. Random effects Poisson regression was used to examine temporal trends.The SHR for all causes and non alcoholic liver disease was two-fold higher in the HCV cohort compared with the HBV cohort (SHRs 1.4 (95%CI: 1.4-1.4) v 0.6 (95%CI: 0.6-0.6) and 14.0 (95%CI: 12.7-15.4) v 5.4 (95%CI: 4.5-6.4), respectively), whilst the opposite was seen for primary liver cancer (SHRs 16.2 (95%CI: 13.8-19.1) v 29.1 (95%CI: 24.7-34.2)). HIV co-infection doubled the SHR except for primary liver cancer in the HCV/HIV cohort. In HBV and HCV mono-infected cohorts, all cause hospitalization rates declined and primary liver cancer rates increased, whilst rates for non alcoholic liver disease increased by 9% in the HCV cohort but decreased by 14% in the HBV cohort (P < 0.001).Hospital-related morbidity overall and for non alcoholic liver disease was considerably higher for HCV than HBV. Improved treatment of advanced HBV-related liver disease may explain why HBV liver-related morbidity declined. In contrast, HCV liver-related morbidity increased and improved treatments, especially for advanced liver disease, and higher levels of treatment uptake are required to reverse this trend.Chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) is associated with increased morbidity and mortality. Several data linkage studies have reported an excess burden of hepatocellular carcinoma (HCC) and mortality, particularly from advanced liver disease [1-5]. They also highlight an increased disease burden associated with HBV/HIV, HCV/HIV and HBV/HCV co-infection [2-4,6]. These population-based studies outline the relative incidence of cancer and mortality, but there are limited data comparing the impact of HBV and HCV infection on hospitalization rates. The one published study compared the average
Hip Structural Parameters over 96 Weeks in HIV-Infected Adults Switching Treatment to Tenofovir-Emtricitabine or Abacavir-Lamivudine
Hila Haskelberg, Nicholas Pocock, Janaki Amin, Peter Robert Ebeling, Sean Emery, Andrew Carr, STEAL study investigators
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0094858
Abstract: Background Therapy with tenofovir is associated with lower bone mineral density (BMD), higher markers of bone turnover and increased fracture risk in HIV-infected adults. Bone structural parameters generated by hip structural analysis may represent a separate measure of bone strength, but have not been assessed in HIV. Methods Dual-energy X-ray absorptiometry (DXA) scans from 254 HIV-infected adults randomised to simplify their existing dual nucleoside analogue reverse transcriptase inhibitor therapy to coformulated tenofovir-emtricitabine or abacavir-lamivudine were analysed using DXA-derived hip structural analysis software. Hip structural parameters included femoral strength index, section modulus, cross-sectional area, and cross-sectional moment of inertia. We used one-way ANOVA to test the relationship between nucleoside analogue type at baseline and structural parameters, multivariable analysis to assess baseline covariates associated with femoral strength index, and t-tests to compare mean change in structural parameters over 96 weeks between randomised groups. Results Participants taking tenofovir at baseline had lower section modulus (?107.3 mm2, p = 0.001), lower cross-sectional area (?15.01 mm3, p = 0.001), and lower cross-sectional moment of inertia (?2,036.8 mm4, p = 0.007) than those receiving other nucleoside analogues. After adjustment for baseline risk factors, the association remained significant for section modulus (p = 0.008) and cross-sectional area (p = 0.002). Baseline covariates significantly associated with higher femoral strength index were higher spine T-score (p = 0.001), lower body fat mass (p<0.001), lower bone alkaline phosphatase (p = 0.025), and higher osteoprotegerin (p = 0.024). Hip structural parameters did not change significantly over 96 weeks and none was significantly affected by treatment simplification to tenofovir-emtricitabine or abacavir-lamivudine. Conclusion In this population, tenofovir use was associated with reduced composite indices of bone strength as measured by hip structural analysis, but none of the structural parameters improved significantly over 96 weeks with tenofovir cessation. Trial Registration ClinicalTrials.gov NCT00192634
Differences in Lipid Measurements by Antiretroviral Regimen Exposure in Cohorts from Asia and Australia
Amit C. Achhra,Janaki Amin,Jennifer Hoy,Junko Tanuma,Thira Sirisanthana,David Nolan,Tuti Merati,Michelle Giles
AIDS Research and Treatment , 2012, DOI: 10.1155/2012/246280
Abstract: We explored the mean differences in routinely measured lipids (total cholesterol, triglycerides, and high-density lipoprotein cholesterol) according to exposure to different combination antiretroviral regimens in Asian ( ) and Australian (predominantly Caucasian, ) cohorts. The regimen was defined as at least 3 antiretroviral drugs with at least 2 nucleoside-reverse transcriptases (NRTIs) and either of at least one protease inhibitor (PI) or non-nucleoside-reverse transcriptases (NNRTIs). We categorised cART regimens as: NRTIs as tenofovir based or not; NNRTIs as nevirapine or efavirenz (but not both); and PI as atazanavir based or not. We found that the impact of various antiretroviral regimens on lipids in Asian and Australian cohorts was only different by cohort for total cholesterol ( for interaction between regimen and cohort: <0.001) but not in case of other lipids ( for interaction: >0.05). The differences in total cholesterol were however small and unlikely to be of clinical significance. Overall, tenofovir with nevirapine or atazanavir was associated with the most favorable lipids, while the PI regimens without tenofovir and atazanavir were associated with least favorable lipids. We conclude that the impact of various ART regimens on lipids is largely similar in Asian and Australian cohorts and that the newer drugs such as tenofovir and atazanavir are likely to provide similar benefit in terms of lipid profiles in both populations. 1. Introduction Combination antiretroviral therapy (cART) for HIV infection is associated with adverse changes in lipid profiles and can include elevation in total cholesterol and triglycerides, which may increase the risk of coronary heart disease (CHD) [1–4]. Moreover, different classes of cART and drugs within each class have differential impacts on lipids [2]. Protease-inhibitors (PIs) are associated with more significant changes in lipid profile than nucleoside and nonnucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs, resp.) [2, 3, 5]. And within NNRTI class, efavirenz (EFV) is associated with greater changes in the lipid profile than nevirapine (NVP) [2, 5, 6]. Also tenofovir (TDF) and atazanavir (ATV) are known to have a favorable impact on lipids [5, 7, 8]. Drugs such as TDF, EFV, and ATV are becoming increasingly available in low-middle-income countries, including Asia [9, 10]. However, much of our knowledge about the relative impact of different cART regimens on lipids comes mainly from clinical trials and cohort studies from European or North-American settings [2, 4, 7, 8]. The impact of cART
Changes in Bone Turnover and Bone Loss in HIV-Infected Patients Changing Treatment to Tenofovir-Emtricitabine or Abacavir-Lamivudine
Hila Haskelberg, Jennifer F. Hoy, Janaki Amin, Peter R. Ebeling, Sean Emery, Andrew Carr, STEAL Study Group
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0038377
Abstract: Background Those receiving tenofovir/emtricitabine (TDF-FTC) had greater bone loss compared with abacavir/lamivudine (ABC-3TC) in a randomized simplification trial (STEAL study). Previous studies associated increased bone turnover and bone loss with initiation of antiretroviral treatment, however it is unclear whether change in bone mineral density (BMD) was a result of specific drugs, from immune reconstitution or from suppression of HIV replication. This analysis determined predictors of BMD change in the hip and spine by dual-energy x-ray absorptiometry in virologically suppressed participants through week 96. Methodology/Principal Findings Bone turnover markers (BTMs) tested were: formation [bone alkaline phosphatase, procollagen type 1 N-terminal propeptide (P1NP)]; resorption (C-terminal cross-linking telopeptide of type 1 collagen [CTx]); and bone cytokine-signalling (osteoprotegerin, RANK ligand). Independent predictors of BMD change were determined using forward, stepwise, linear regression. BTM changes and fracture risk (FRAX?) at week 96 were compared by t-test. Baseline characteristics (n = 301) were: 98% male, mean age 45 years, current protease-inhibitor (PI) 23%, tenofovir/abacavir-na?ve 52%. Independent baseline predictors of greater hip and spine bone loss were TDF-FTC randomisation (p≤0.013), lower fat mass (p-trend≤0.009), lower P1NP (p = 0.015), and higher hip T score/spine BMD (p-trend≤0.006). Baseline PI use was associated with greater spine bone loss (p = 0.004). TDF-FTC increased P1NP and CTx through Wk96 (p<0.01). Early changes in BTM did not predict bone loss at week 96. No significant between-group difference was found in fracture risk. Conclusions/Significance Tenofovir/emtricitabine treatment, lower bone formation and lower fat mass predicted subsequent bone loss. There was no association between TDF-FTC and fracture risk.
Characterization of Transcription Factor Phenotypes within Antigen-Specific CD4+ T Cells Using Qualitative Multiplex Single-Cell RT-PCR
Chansavath Phetsouphanh, Yin Xu, Janaki Amin, Nabila Seddiki, Francesco Procopio, Rafick Pierre Sekaly, John J. Zaunders, Anthony D. Kelleher
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0074946
Abstract: Current research on antigen specific CD4+ T cells indicates that there is functional and phenotypic heterogeneity within these populations, but the extent of this heterogeneity is poorly described. The CD134/CD25 assay allows live isolation of antigen specific cells in vitro for down-stream molecular analysis. Antigen specific CD4+ T cells were examined at the molecular level by lineage specific transcription factor profiling using qualitative multiplex single cell RT-PCR and Lock Nucleic Acid (LNA) probes allowed unbiased amplification and delineation of expression of Tbx21, Gata3, Rorc, Foxp3 and Bcl-6. It overcomes the limitations of previous assays by allowing identification of transcription factor mRNA in single antigen specific cells with high sensitivity (down to 10 femtograms) and specificity. Patterns of responses can be robustly characterized using <200 cells based on exact binomial calculations. These results are reproducible with a CV of ≈6%. The patterns of heterogeneity are stable within an individual antigen specific response but vary between responses to different antigens. Responses to CMV have a Th1 predominant profile (35.6% of responding cells expressing tbx21) whereas responses to Tetanus Toxoid have a Th2 biased profile (22% of responding cells expressing gata3), with unexpectedly high levels of Treg cells found in both populations. Here we describe a methodology that allows live isolation of Ag specific cells and transcription factor profiling at a single cell level to robustly delineate the different CD4+ T cell subsets within this population. This novel method is a powerful tool that can be used to study CD4+ T cell heterogeneity within extremely small populations of cells and where cell numbers are limited.
HLA Alleles Association with Changes in Bone Mineral Density in HIV-1-Infected Adults Changing Treatment to Tenofovir-Emtricitabine or Abacavir-Lamivudine
Hila Haskelberg, Damien V. Cordery, Janaki Amin, Anthony D. Kelleher, David A. Cooper, Sean Emery, on behalf of the STEAL Study Group
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0093333
Abstract: Background There are limited data regarding the influence of human leukocyte antigen (HLA) polymorphisms on reduced bone mineral density (BMD). We investigated the relationship between HLA supertypes and BMD in HIV-infected adults changing their existing treatment to tenofovir-emtricitabine (TDF-FTC) or abacavir-lamivudine (ABC-3TC) in the STEAL study. Methods Lumbar spine and right hip BMD were measured by Dual-energy X-ray absorptiometry (DXA). HLA genotypes at the 2-digit level were classified into class I and II supertypes. Student's t-tests were used to test the association between HLA supertypes and changes in hip and spine BMD over 96 weeks for the whole cohort and stratified by randomised groups. The relationship between HLA supertypes and BMD was also assessed in the subgroup of participants that were na?ve to both ABC and TDF at study entry. Results Class II supertypes were mainly associated with hip BMD change. Overall, compared to participants not carrying HLA-DQ3, participants expressing DQ3 had less bone loss over 96 weeks at both the hip and spine (hip: 0.003 vs. ?0.006 g/cm2, 95%CI 0.002 to 0.017, p = 0.016; spine: 0.006 vs. ?0.006 g/cm2, 95%CI 0.001 to 0.023, p = 0.041). In participants that were na?ve to both ABC and TDF at baseline and randomised to TDF-FTC, DQ3 was significantly associated with less bone loss compared with those not carrying DQ3 (hip: 0.001 vs. ?0.032 g/cm2; diff 0.033; 95%CI 0.017 to 0.049; p<0.001; spine: 0.007 vs. ?0.023 g/cm2; diff 0.035; 95%CI 0.014 to 0.056; p = 0.001). Conclusions In this cohort of HIV-infected adults, there was an association between bone status and HLA supertypes, particularly HLA-DQ3. Trial Registration Clinicaltrials.gov NCT00192634
Inaccurate Ascertainment of Morbidity and Mortality due to Influenza in Administrative Databases: A Population-Based Record Linkage Study
David J. Muscatello, Janaki Amin, C. Raina MacIntyre, Anthony T. Newall, William D. Rawlinson, Vitali Sintchenko, Robin Gilmour, Sarah Thackway
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0098446
Abstract: Background Historically, counting influenza recorded in administrative health outcome databases has been considered insufficient to estimate influenza attributable morbidity and mortality in populations. We used database record linkage to evaluate whether modern databases have similar limitations. Methods Person-level records were linked across databases of laboratory notified influenza, emergency department (ED) presentations, hospital admissions and death registrations, from the population (~6.9 million) of New South Wales (NSW), Australia, 2005 to 2008. Results There were 2568 virologically diagnosed influenza infections notified. Among those, 25% of 40 who died, 49% of 1451 with a hospital admission and 7% of 1742 with an ED presentation had influenza recorded on the respective database record. Compared with persons aged ≥65 years and residents of regional and remote areas, respectively, children and residents of major cities were more likely to have influenza coded on their admission record. Compared with older persons and admitted patients, respectively, working age persons and non-admitted persons were more likely to have influenza coded on their ED record. On both ED and admission records, persons with influenza type A infection were more likely than those with type B infection to have influenza coded. Among death registrations, hospital admissions and ED presentations with influenza recorded as a cause of illness, 15%, 28% and 1.4%, respectively, also had laboratory notified influenza. Time trends in counts of influenza recorded on the ED, admission and death databases reflected the trend in counts of virologically diagnosed influenza. Conclusions A minority of the death, hospital admission and ED records for persons with a virologically diagnosed influenza infection identified influenza as a cause of illness. Few database records with influenza recorded as a cause had laboratory confirmation. The databases have limited value for estimating incidence of influenza outcomes, but can be used for monitoring variation in incidence over time.
Switching Virally Suppressed, Treatment-Experienced Patients to a Raltegravir-Containing Regimen Does Not Alter Levels of HIV-1 DNA
Yu Ming Paul Lam, Kristin L. McBride, Janaki Amin, Damien V. Cordery, Anthony D. Kelleher, David A. Cooper, Kersten K. Koelsch
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0031990
Abstract: Background Current HIV-1 antiretroviral therapy (ART) greatly reduces virus replication but does not significantly affect the viral reservoir. Raltegravir, a recently introduced integrase inhibitor, could, at least theoretically, reduce residual viremia in patients on ART and affect the viral reservoir size. The aim of this study was to assess whether switching therapy in treatment-experienced patients that were virally suppressed to a raltegravir-containing regimen reduces the size of the viral reservoir, and if such treatment leads to a change in levels of HIV 2-LTR circles in this patient group. Methods 14 ART experienced individuals with a suppressed viral load (<50 HIV-1 RNA copies/mL plasma) at baseline (for at least 2 months) were switched to a raltegravir-containing regimen. Blood samples were taken at baseline and at ≥2 timepoints up to 48±6 weeks. Levels of total HIV-1 DNA and 2-LTR circles in peripheral blood mononuclear cells (PBMCs) were measured using real-time PCR assays. Results There was no significant change in HIV-1 total DNA levels over the study duration (p = 0.808), median slope 0.24 (conservative nonparametric 95% CI: ?11.78, 26.23). Low levels of 2-LTR circles were detected in 2 patients. One had 16 copies/106 PBMCs at baseline and the other had 34 copies/106 PBMCs at week 51. Conclusions The switch to a raltegravir containing regimen was not associated with a significant change in HIV-1 total DNA levels in this cohort. There were no observed changes in the levels of HIV-1 2-LTR circles associated with raltegravir treatment initiation.
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